Design and Optimization of 1H-1,2,3-Triazole-4-carboxamides as Novel, Potent, and Selective Inverse Agonists and Antagonists of PXR.

ABSTRACT: The pregnane X receptor (PXR) is a key regulator of drug metabolism. Many drugs bind to and activate PXR, causing adverse drug responses. This suggests that PXR inhibitors have therapeutic value, but potent PXR inhibitors have so far been lacking. Herein, we report the structural optimization of a series of 1H-1,2,3-triazole-4-carboxamides compounds that led to the discovery of compound 85 as a selective and the most potent inverse agonist and antagonist of PXR, with low nanomolar IC₅₀ values for binding and cellular activity. Importantly, compound 89, a close analog of 85, is a selective and pure antagonist with low nanomolar IC₅₀ values for binding and cellular activity. This study has provided novel, selective, and most potent PXR inhibi

SUBMITTER: Li Y 

PROVIDER: S-EPMC9789209 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature